Intrauterine growth retardation (“IUGR”) is a syndrome whereby the size or growth rate of a fetus is unusually small for the gestational age of the fetus. Fetuses weighing below the 10th percentile for their gestational age, are by definition afflicted with IUGR. IUGR can result from a wide variety of causes, all of which result in the failure of a fetus to exhibit a normal rate of growth. Small for gestational age (SGA) babies are defined as birth weight and/or length at least 2 standard deviations below the mean for gestational age (Lee et al., 2003, Pediatrics 111: 1253-1261). Although some fetuses that are small for their gestational age can be simply constitutionally small and not otherwise unhealthy, other causes, such as placental insufficiency, infection, and genetic disorders, can result in significant perinatal morbidity and mortality. The individuals so affected are also more likely to suffer from abnormal structure, function, and disease in later life. Any method to reverse or ameliorate IUGR can thus provide significant benefits to these offspring.
A number conditions have been identified as increasing the risk that a fetus will display IUGR. Often, the primary effect of these conditions is to cause placental insufficiency (Lepercq and Mahieu-Caputo, 1998, Horm. Res. 49(suppl 2): 14-19). These conditions include maternal weight and height prior to pregnancy and low weight gain during the pregnancy; maternal history of stillbirth, neonatal death, and previous offspring with low birth weight; maternal activities during pregnancy, such as smoking, alcohol and drug use, and poor nutrition; early intrauterine infections; maternal medical diseases; multiparous pregnancies; and various complications arising during pregnancy.
The maternal endocrine system likely has a role in controlling fetal growth rates, e.g., by regulating the placental nutrient supply. Insulin and insulin-like growth factor I have been shown to be involved in this process (Gluckman et al., 1990, Acta Paediatr. Scand. [Suppl] 367:105-110; U.S. Pat. No. 5,420,111).
Recent studies have suggested that VEGF activity is critical to normal placental development (reviewed in Tsatsaris et al., 2003, J Clin Endocrinol Metab 88:5555-5563). The imbalance between expression of members of the VEGF family (including VEGF-A and placental growth factor (PlGF)) and their soluble and cell-associated receptors (s-flt and fit, respectively) may play a role in conditions associated with placental insufficiency. It is currently believed that upregulation of s-fit, which can antagonize VEGF and PlGF activity, shifts the balance of this family toward anti-angiogenic activity, thus interfering with normal vascular development of the placenta. It is also believed that inadequate placental perfusion may be upstream of maternal disorders, such as preeclampsia (Bdolah et al., 2004, Semin Nephrol 24:548-556), HELLP (Cho et al., 2003, J Korean Med Sci 18:402-428), as well as abnormal or inadequate fetal growth (Ahmed and Perkins, 2000, Baillieres Best Pract Res Clin Obstet Gynecol 14:981-998). Treatments that can prolong pregnancy are likely to be beneficial in allowing both short-term fetal growth and obviation of long term developmental impairment.
Because of the current lack of effective treatments for IUGR or placental insufficiency, there is a strong need to develop new therapeutic approaches for this condition.